Is CIB2 p.Arg186Gln (c.557G>A) pathogenic?

CIB2 p.Arg186Gln (c.557G>A) is classified Conflicting classifications of pathogenicity in CIB2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-06-06). AlphaMissense: likely pathogenic (0.9348); Very rare (popmax 0.000932%, nfe).

How common is CIB2 p.Arg186Gln (c.557G>A) in the general population?

CIB2 p.Arg186Gln (c.557G>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about CIB2 p.Arg186Gln (c.557G>A)?

AlphaMissense predicts likely pathogenic (score 0.9348) — an in-silico prediction, not a clinical call.

CIB2 p.Arg186Gln

c.557G>A · rs1281648597 · VCV505421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9348	likely pathogenic
REVEL	0.332	indeterminate
SaProt	LLR -10.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.21	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 26 kb · p 0.17 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,964 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000753% 11/1,461,758 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CIB2
Protein: p.Arg186Gln
Coding: c.557G>A
MANE Select: NM_006383
dbSNP: rs1281648597
Type: single nucleotide variant
Location: chr15:78105318 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71 · 1 PDB
Residue 186: a UniProt-annotated variant site (in dfnb48); a UniProt-annotated variant site (in dfnb48; uncertain significance); a UniProt-annotated variant site (in dfnb48; inhibits the ability to decrease atp-induced calcium release; decreases interaction with tmc1 and tmc2; does not affect the localization in the cuticular plate or to the tip of stereocilia; does not affect binding with whrn)

Full CIB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIB2 p.Arg186Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
CIB2 p.Arg186= Likely benign ★ same residue
CIB2 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same type
CIB2 p.Arg33Ter Pathogenic ★★ same type
CIB2 p.Arg66Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
CIB2 c.198+3A>G Uncertain significance ★★ same type
CIB2 p.Ala108Thr Uncertain significance ★★ ⚠ same type
CIB2 p.Ala76Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cib2-p-arg186gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown